Remedies for drug addiction

ABSTRACT

A method for treating drug dependence comprising administering, as the active ingredient, an opioid κ receptor agonist of a compound represented by the following formula, is disclosed                    
     wherein A and the R terms are herein defined.

This application is the national phase under 35 U.S.C. §371 of PCTInternational Application No. PCT/JP98/03937 which has an Internationalfiling date of Sep. 2, 1998 which designated the United States ofAmerica.

TECHNICAL FIELD

The present invention relates to a remedy for drug dependence. Inaddition, the present invention relates to a dopamine-release inhibitor,in which dopamine is heavily associated with drug dependence.

BACKGROUND ART

When a person repeatedly take a natural substance such as opium,cocaine, or marijuana, or takes a specific drug such as heroin,barbiturates, or stimulants, it is impossible to suddenly withhold thedrug. Then, their major goal in life tends to focus on obtaining thesesubstances and drugs. In addition, brutal crimes may be provoked.Moreover, serious incidents, which affect the state of the nation, mayalso be provoked. There is substantially the same underlying cause inthese problems of drug abuse as in habituation to consuming commonsubstances, for example, alcohol or tobacco.

World Health Organization (WHO) defines both drug dependence and drugabuse. That is, drug dependence is defined as follows: “A state, psychicand sometimes also physical, resulting from the interaction between aliving organism and a drug, characterized by behavioural and otherresponses that always include a compulsion to take the drug on acontinuous or periodic basis in order to experience its psychic effects,and sometimes to avoid the discomfort of its absence.” Drug dependenceis further classified as a state of psychic dependence on a drug, thatis, psychic dependence, or a state in which a body is adapted toexisting the drug, that is, physical dependence.

The WHO classifies drugs which become addictive into nine groups, thatis, 1. alcohol, 2. amphetamines, 3. barbiturates, 4. marijuana, 5.cocaine, 6. hallucinogens, 7. khat, 8. opiates, and 9. organic solvents.All the drugs classified into the nine groups, to which dependence maybe developed, also show psychic dependence. In addition, three groups,that is, opiates, barbiturates, and alcohol, may be accompanied byphysical dependence. At present, among these drugs which developdependence, opiates, barbiturates, cocaine, and amphetamines areavailable for clinical use.

With respect to international laws relevant to dependence-producingdrugs, there are the “Single Convention Treaty on Narcotic Drugs” (1961)and the “The Convention on Psychotropic Substances” (1971). Under theabove-mentioned two treaties, all countries are to make a concertedeffort to conduct strict inspections of international distribution ofnarcotics and prevent narcotics from being illicitly distributed. Asdrug abuse expands throughout the world, international regulationbecomes stricter. Recently, drugs capable of being abused have increasedboth in kind and in variety. On the other hand, since exchange of goodsand travel have been internationally increased and an informationnetwork has been developed, cases of psychotropic drug abuse haveincreased in addition to cases of narcotics, marijuana, and stimulantabuse. In addition, the drug abuse epidemic area is also spreadingthroughout the world. For example, recently, narcotics abuse hassignificantly increased in countries in North America, Central and SouthAmerica, Southeast Asia, Middle East, and Europe. In particular, thecocaine abuse problem has become a deep social ill in South America,North America, Europe and the like. On the other hand, the stimulantsabuse problem has also spread in Japan, North America, and Europe.Furthermore, at present, other psychotropic drug abuses have alsoincreased in these countries.

With respect to a remedy for drug dependence, particular drugs are notusually applied other than drugs used for symptomatic treatment. Themain treatment is psychotherapy which is aimed at self-awareness,replacing a dependence-producing drug with a drug which is lessdependent, or gradually-decreasing drug treatment. With respect tosymptomatic treatment, antianxiety drugs such as diazepam andflunitrazepam, and short-acting barbiturates have been initially usedfor treatment for acute toxipathy. An antipsychotic agent such ashaloperidol or phenotiazines has been used for treatment of acutepsychoses. However, the items of concern involve adverse effect such aspsychogenesis peculiar to central nervous system sedatives in treatmentsusing drugs such as diazepam, flunitrazepam, or barbiturates. The itemsof concern involve adverse effects such as psychogenesis peculiar topsychotropic drugs in treatment using drugs such as haloperidol orphenotiazines, so that there is the possibility that drug dependence isreplaced by psychotropic drug dependence. (Alcohol and Drug Dependence,Basic Research and Clinical Research, Kenshirou Oohara, SakutarouTadokoro (Kaneharasyuppan); Drug Dependence, Mitsumoto Satou, SusumuFukui (Sekaihokentuusinsya)).

A drug reaction in which after the drug is given to a living organism,drug-seeking behavior or drug-taking behavior are more frequentlyinduced, is defined as a reinforcing effect or a reward effect. Theseeffects caused by the dependence-producing drugs are closely related toan intracerebral dopamine nervous system. The intracerebral dopaminenervous system is roughly classified into two systems, that is, anigrostriatal system and a mesolimbic system which projects from anventral tagmental area to a nucleus accumbens. There have been manyreports which indicate the reinforcing effect or the reward effect isrelated to the mesolimbic system.

For example, cocaine, that is a central nervous system stimulant,affects neurosynapses in the nucleus accumbens so as to acceleratedopamine release from dopamine neuroterminals and to inhibit the uptakethereof, so that an amount of dopamine which binds to dopamine receptorsincreases and nerve activities are facilitated. Therefore, onset ofpsychic dependence seems to be triggered. On the other hand, sinceopioid κ receptor agonists inhibit dopamine release in the nucleusaccumbens (Japanese Journal of Pharmacology. 109: 165-173, 1997), theopioid κ receptor agonists may suppress the reward effect of cocaine andhold promise as a remedy for psychic cocaine dependence. At present,opioid κ receptor agonists, however, have not been applied in practicaluse for a remedy for cocaine dependence.

In addition, with respect to the relationship between opiates and theirreward effect in drug dependence, it is known that opiates not only haveanalgesic activity but also function as a chemical mediator for thereward effect. The opioid receptors are classified into μ, δ, and κreceptors. Among them, it was initially reported that μ receptoragonists such as morphine showed the reward effect (T. Suzuki et al.,Eur. J. Pharmacol. 205, 85, 1991). It has been reported that μ or δreceptor agonistic endogenous opioid peptides such as β-endorphins andenkephalins also show the reward effect (T. Suzuki et al., Jpn. J.Pharmacol. 66, 131, 1994).

Furthermore, opioid receptors are known to relate to a dopamine nervoussystem. The opioid μ receptors are distributed in high density in aventral tegmental area in which cell sonata of the mesolimbic systemexist, so that they inhibit an inhibitory γ-aminobutyric acid (GABA)nervous system, that is, interneurons, and stimulate the mesolimbicsystem. As a result, it is suggested that when a μ receptor agonist issystemically administered or microinjected into the ventral tegmentalarea, dopamine release in the projected nucleus accumbens seems to besignificantly increased. On the other hand, δ, and κ opioid receptorsare known to be distributed in high density in the projected area, thatis, nucleus accumbens in the mesolimbic system. When δ opioid receptorsare activated, similarly to μ opioid receptors, they seem to inhibit theinhibitory GABA nervous system, that is, interneurons, and to facilitatedopamine release in the nucleus accumbens. In contrast, κ receptoragonists do not show the reward effect in a drug self-administration (T.Suzuki et al., Brain Res. 602, 45, 1993). As described above, it isreported that when a κ receptor agonist such as U-50488H which activatesκ receptors is administered, dopamine release from the nucleus accumbensis inhibited (Japanese Journal of Pharmacology. 109: 165-177, 1997). Inaddition, animal tests show that -the reward effect induced by μ or δreceptor agonists is inhibited by κ receptor agonists such as U-50488H(M. Funada et al., Neuropharmacology, 32, 1315, 1993). That is,activation of κ receptors enhances an analgesic effect of μ or δreceptor agonists, but inhibits the reward effect. On the basis of thesefacts, opioid κ receptor agonists seem to be promising remedies forpsychic dependence to opioid μ receptor agonists. Furthermore, it isreported that opioid κ receptor antagonists enhance development ofphysical dependence, but certain opioid κ receptor agonists inhibitdevelopment of physical dependence (Suzuki, T. et al., Eur. J.Pharmacol. 213, 91, 1991). At present, opioid κ receptor agonists,however, have not been adapted to remedies for opioid μ receptoragonists dependence and also have not been applied in practical use.

In a reported case of opioids and nicotine dependence (tobaccoaddiction), naloxone, that is, a narcotic antagonist (μ receptorantagonist), is effective for a reduction in intake of tobacco ofchronic smokers for three hours in a double blind test and a cross-overtest with a drug and its placebo (Karras, A. et al., Life Science, 27,1541, 1980). In contrast, it is reported that naloxone accelerates awithdrawal syndrome in rats with nicotine dependence, and morphine (a μreceptor agonist) inhibits the withdrawal syndrome after anadministration of nicotine (Malin, D. H. et al., Psychopharmacology,112, 339, 1993). In addition, it is reported that nicotinic receptorsexist at terminals of a dopamine nervous system in the nucleusaccumbens, and relate to facilitation of dopamine release (Di Chiara, G.et al., Natl. Acad. Sci. USA, 85, 5274, 1988). Furthermore, it isreported that a reduction in the amount of dopamine in the nucleusaccumbens follows the cessation of the administration of nicotine torats with nicotine dependence (Fung, Y. K. et al., J. Pharm. Pharmacol.,41, 66, 1989). In contrast, inhibitory activity against nicotinedependence of κ receptor agonists including dynorphin which is anendogenous opioid peptide having κ receptor agonistic activity,particularly inhibitory activity against physical dependence, has notbeen clear.

In addition, there have been many reports that psychic dependence on adrug such as barbiturates, benzodiazepines which are central nervoussystem sedatives, amphetamine, methamphetamine, and the like which arestimulants, phencyclidine which is a hallucinogen, and alcohol iscontrolled by a mechanism of dopamine increase (Yanagita T., NipponYakugaku Zasshi—Folia Pharmacologica Japonica. 100 (2): 97-107, 1992Aug.; Samochowiec J., Annales Academiae Medicae Stetinensis. 40: 195-217(1994); Kuperman D I. et al., Brain Research. 771 (2): 221-7 (1997);Heron C. et al. European Journal of Pharmacology. 264 (3): 391-8 (1994);Saad S F. et al. Journal of Pharmacy & Pharmacology. 49 (3): 322-8(1997); Costall B. et al., Arzneimittel-Forschung. 42 (2A): 246-9(1992)). On the basis of the above-described facts, drugs havingactivity to inhibit dopamine release from the nucleus accumbens mayinhibit the reward effect caused by these dependence-producing drugs andmay be a promising remedy for psychic dependence.

In addition, existing highly selective κ receptor agonists such asU-50488H prove not to develop drug dependence which is a characteristicof morphine or the like having reactivity to a μ receptor (T. Suzuki etal., Eur. J. Pharmacol., 205, 85, 1991).

An object of the present invention is to provide a remedy for drugdependence with little adverse effects, which depresses not only onsetof psychic dependence but also physical dependence due to controllingthe expression mechanism of the reward effect of dependence-producingdrugs in a treatment for drug dependence caused by cocaine, opioid μagonists, nicotine, alcohol, stimulants, barbiturates, benzodiazepines,or hallucinogens. The above-mentioned treatment is different from theconventional symptomatic treatments.

DISCLOSURE OF INVENTION

The present invention provides a remedy for drug dependence in which theactive ingredient is an opioid κ receptor agonist. In addition, thepresent invention also provides a dopamine-release inhibitor in whichthe active ingredient is an opioid κ receptor agonist.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 and FIG. 2 show inhibitory effects of opioid κ receptor agonistsagainst development of psychic dependence induced by an opioid μreceptor agonist.

FIG. 3 shows inhibitory effects of an opioid κ receptor agonist againstdevelopment of psychic dependence induced by an opioid μ receptoragonist, and a result of an antagonism test on an opioid κ receptoratagonist.

FIG. 4 shows effects of an opioid κ receptor agonist on analoxone-induced withdrawal syndrome (a weight reduction).

FIG. 5 and FIG. 6 show inhibitory effects of opioid κ receptor agonistsagainst development of psychic dependence induced by cocaine.

FIG. 7 shows inhibitory effects of an opioid κ receptor agonist againstdevelopment of psychic dependence induced by cocaine.

FIG. 8 shows a drug discrimination effect of opioid κ receptor agonist.

FIG. 9 shows an effect of an opioid κ receptor antagonist on aninhibition of cocaine discrimination by an opioid κ receptor agonist.

FIG. 10 shows inhibitory effects on a mecamylamine-induced nicotinewithdrawal syndrome by an opioid κ receptor agonist.

FIG. 11 shows inhibitory effects on dopamine release by an opioid κreceptor agonist.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention includes a remedy for nicotine dependence in whichan active ingredient is an opioid κ receptor agonist. In this case, theopioid κ receptor agonist is a compound which is selective towards theopioid κ receptor even if the compound has any specific chemicalstructure. That is, guinea-pig ileum (GPI) and mouse vas deference (MVD)tests are performed in order to assess agonistic activity on an opioidreceptor (assessment of an inhibitory effect on constriction induced byelectric stimulation of guinea-pig ileum and mouse vas deference). Then,the same procedure is performed in the presence of an opioid receptorantagonist, in which the antagonist is selective towards μ, δ, or κreceptor, so as to calculate Ke values. When the Ke values of thereceptors are compared with each other, a compound, in which Keμ isgreater than Keκ and Keδ is simultaneously greater than Keκ, is moreselective towards a κ receptor than to a μ and a δ receptor.

Specifically, the compound is an opioid κ receptor agonist orpharmacologically acceptable acid-addition salts thereof represented bythe general formula (I):

wherein

is a double bond, or a single bond; R¹ is an alkyl group having from 1to 5 carbon atoms, a cycloalkylalkyl group having from 4 to 7 carbonatoms, a cycloalkenylalkyl group having from 5 to 7 carbon atoms, anaryl group having from 6 to 12 carbon atoms, an aralkyl group havingfrom 7 to 13 carbon atoms, an alkenyl group having from 4 to 7 carbonatoms, an allyl group, a furan-2 -ylalkyl group having from 1 to 5carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5 carbonatoms; R₂ is a hydrogen atom, a hydroxy group, a nitro group, analkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkyl group having from 1 to 5carbon atoms, or —NR⁹R¹⁰; R⁹ is a hydrogen atom or an alkyl group havingfrom 1 to 5 carbon atoms; R¹⁰ is a hydrogen atom, an alkyl group havingfrom 1 to 5 carbon atoms, or —C(═O)R¹¹; R¹¹ is a hydrogen atom, a phenylgroup, or an alkyl group having from 1 to 5 carbon atoms; R³ is ahydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is—XC(═Y)—, —XC(═Y)Z-, —X—, or —XSO₂— (wherein X, Y and Z are,independently of one another, NR⁴, S, or 0; and R⁴ is a hydrogen atom, astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms, or an aryl group having from 6 to 12 carbon atoms; and R⁴ may beidentical or different in the formula); B is a valence bond, astraight-chain or branched-chain alkylene group having from 1 to 14carbon atoms (wherein the alkylene group may be substituted by one ormore substituents selected from the group consisting of an alkoxy grouphaving from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, abromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group, and a phenoxygroup, and wherein one to three methylene groups of the alkylene groupmay be replaced with carbonyl groups), a straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds and having from 2 to 14 carbonatoms (wherein the acyclic unsaturated hydrocarbon may be substituted byone or more substituents selected from the group consisting of an alkoxygroup having from 1 to 5 carbon atoms, an alkanoyloxy group having from1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group, and a phenoxygroup, and wherein one to three methylene groups of the acyclicunsaturated hydrocarbon maybe replaced with carbonyl groups), or astraight-chain or branched-chain saturated or unsaturated hydrocarboncontaining from one to five thioether, ether, and/or amino bonds andhaving from 1 to 14 carbon atoms (wherein no hetero atoms are bondeddirectly to A, and one to three methylene groups of the hydrocarbon maybe replaced with carbonyl groups); and R⁵ is a hydrogen atom or anorganic group having a basic skeleton selected from the group consistingof the following formulas:

Organic Groups Represented by R⁵

wherein the organic group may have at least one substituent selectedfrom the group consisting of an alkyl group having from 1 to 5 carbonatoms, an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxygroup having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom,a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitrogroup, a cyano group, an isothiocyanate group, a trifluoromethyl group,a trifluoromethoxy group, and a methylenedioxy group; R⁶ is a hydrogenatom; R⁷is a hydrogen atom, a hydroxy group, an alkoxy group having from1 to 5 carbon atoms, or an alkanoyloxy group having from 1 to 5 carbonatoms, or R⁶ and R⁷are —O—, —CH₂—, —S— together; R⁸ is a hydrogen atom,an alkyl group having from 1 to 5 carbon atoms or an alkanoyl grouphaving from 1 to 5 carbon atoms. And optionally the compound is anopioid κ receptor agonist or pharmacologically acceptable acid-additionsalts thereof represented by the general formula (II):

wherein R denotes two hydrogen atoms, or —O—CH₂CH₂CH₂—; X and Y are,independently of each other, a hydrogen atom or a chlorine atom; Z is Oor S. And optionally the compound is an opioid κ receptor agonist orpharmacologically acceptable acid-addition salts thereof represented bythe general formula (III):

wherein X is a hydrogen atom, a chlorine atom, or a trifluoromethylgroup; Y is a hydrogen atom or a chlorine atom; Z is CH₂, —OCH₂CH₂O—, orNCO₂CH₃. And optionally the compound is an opioid κ receptor agonist orpharmacologically acceptable acid-addition salts thereof represented bythe general formula (IV):

wherein X and Y are, independently of each other, a hydrogen atom or achlorine atom; Z is CH₂, O or S. And optionally the compound is anopioid κ receptor agonist or pharmacologically acceptable acid-additionsalts thereof represented by the general formula (V):

wherein X and Y are, independently of each other, a hydrogen atom or achlorine atom.

In addition, the present invention includes a remedy for nicotinedependence, a remedy for cocaine dependence, a remedy for opioid μreceptor agonist dependence, and a dopamine-release inhibitor in-whichthe active ingredient is an opioid κ receptor agonist orpharmacologically acceptable acid-addition salts thereof represented bythe general formula (I):

wherein

is a double bond, or a single bond; R¹ is an alkyl group having from 1to 5 carbon atoms, a cycloalkylalkyl group having from 4 to 7 carbonatoms, a cycloalkenylalkyl group having from 5 to 7 carbon atoms, anaryl group having from 6 to 12 carbon atoms, an aralkyl group havingfrom 7 to 13 carbon atoms, an alkenyl group having from 4 to 7 carbonatoms, an allyl group, a furan-2 -ylalkyl group having from 1 to 5carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5 carbonatoms; R² is a hydrogen atom, a hydroxy group, a nitro group, analkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy grouphaving from 1 to 5 carbon atoms, an alkyl group having from 1 to 5carbon atoms, or —NR⁹R¹⁰; R⁹ is a hydrogen atom or an alkyl group havingfrom 1 to 5 carbon atoms; R¹⁰ is a hydrogen atom, an alkyl group havingfrom 1 to 5 carbon atoms, or —C(═O)R¹¹; R¹¹ is a hydrogen atom, a phenylgroup, or an alkyl group having from 1 to 5 carbon atoms; R³ is ahydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is—XC(═Y)—, —XC(═Y)Z—, —X—, or —XSO₂— (wherein X, Y and Z are,independently of one another, NR⁴, S, or O; and R⁴ is a hydrogen atom, astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms, or an aryl group having from 6 to 12 carbon atoms; and R⁴ may beidentical or different in the formula); B is a valence bond, astraight-chain or branched-chain alkylene group having from 1 to 14carbon atoms (wherein the alkylene group may be substituted by one ormore substituents selected from the group consisting of an alkoxy grouphaving from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, abromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group, and a phenoxygroup, and wherein one to three methylene groups of the alkylene groupmay be replaced with carbonyl groups), a straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds and having from 2 to 14 carbonatoms (wherein the acyclic unsaturated hydrocarbon may be substituted byone or more substituents selected from the group consisting of an alkoxygroup having from 1 to 5 carbon atoms, an alkanoyloxy group having from1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group, and a phenoxygroup, and wherein one to three methylene groups of the acyclicunsaturated hydrocarbon may be replaced with carbonyl groups), or astraight-chain or branched-chain saturated or unsaturated hydrocarboncontaining from one to five thioether, ether, and/or amino bonds andhaving from 1 to 14 carbon atoms (wherein no hetero atoms are bondeddirectly to A, and one to three methylene groups of the hydrocarbon maybe replaced with carbonyl groups); and R⁵ is a hydrogen atom or anorganic group having a basic skeleton selected from the group consistingof the following formulas:

Organic Groups Represented by R⁵

wherein the organic group may have at least one substituent selectedfrom the group consisting of an alkyl group having from 1 to 5 carbonatoms, an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxygroup having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom,a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitrogroup, a cyano group, an isothiocyanate group, a trifluoromethyl group,a trifluoromethoxy group, and a methylenedioxy group; R⁶ is a hydrogenatom; R⁷ is a hydrogen atom, a hydroxy group, an alkoxy group havingfrom 1 to 5 carbon atoms, or an alkanoyloxy group having from 1 to 5carbon atoms, or R⁶ and R⁷are —O—, —CH₂—, —S— together; R⁸ is a hydrogenatom, an alkyl group having from 1 to 5 carbon atoms or an alkanoylgroup having from 1 to 5 carbon atoms.

In the compound represented by the general formula (I) among the κreceptor agonists in accordance with the present invention, R¹ ispreferably an alkyl group having from 1 to 5 carbon atoms, acycloalkylmethyl group having from 4 to 7 carbon atoms, acycloalkenylmethyl group having from 5 to 7 carbon atoms, a phenylalkylgroup having from 7 to 13 carbon atoms, an alkenyl group having from 4to 7 carbon atoms, an allyl group, a furan-2-yl-alkyl group having from1 to 5 carbon atoms, or a thiophene-2-yl-alkyl group having from 1 to 5carbon atoms; and R¹ is particularly preferably a methyl group, an ethylgroup, a propyl group, a butyl group, an isobutyl group, acyclopropylmethyl group, an allyl group, a benzyl group, or a phenethylgroup.

R² is preferably a hydrogen atom, a hydroxy group, a nitro group, anacetoxy group, a methoxy group, a methyl group, an ethyl group, a propylgroup, an amino group, a dimethylamino group, an acetylamino group, or abenzoylamino group; and R² is particularly preferably a hydrogen atom, ahydroxy group, an acetoxy group, or a methoxy group.

R³ is preferably a hydrogen atom, a hydroxy group, an acetoxy group, ora methoxy group, and is particularly preferably a hydroxy group, anacetoxy group, or a methoxy group.

A is preferably —XC(═Y)— (wherein X is NR⁴, S, or O; Y is O; and R⁴ is ahydrogen atom, or a straight-chain or branched-chain alkyl group havingfrom 1 to 5 carbon atoms), —XC—(═Y)Z—, —X—, or —XSO₂— (wherein X is NR⁴;Y is O or S; Z is NR⁴ or O; and R⁴ is a hydrogen atom, or astraight-chain or branched-chain alkyl group having from 1 to 5 carbonatoms). Specifically, A is —NR⁴C(═O)—, —NR⁴C(═S)—, —NR⁴C(═O)O—, —NR⁴C(═O) NR⁴—, —NR⁴C(═S) NR⁴—, —NR⁴C(═O)S—, —OC(═O)—, —OC(═O)O—, —SC(═O)—,—NR⁴—, —O—, —NR⁴SO₂—, —OSO₂— or the like. Among them, A is preferably—NR⁴C(═O)—, —NR⁴C(═S)—, —NR⁴C (═O)O—, —NR⁴C(═O)NR⁴—, —NR⁴C (═S)NR⁴—, or—NR⁴SO₂—; and more preferably —NR⁴C(═O)— or —NR⁴C(═O)O—.

R⁴ is preferably a hydrogen atom, or a straight-chain or branched-chainalkyl group having from 1 to 5 carbon atoms, and is particularlypreferably a straight-chain or branched-chain alkyl group having from 1to 5 carbon atoms, with a methyl group, an ethyl group, a propyl group,a butyl group or an isobutyl group being the most preferred.

B is preferably a straight-chain alkylene group having from 1 to 10carbon atoms, —(CH₂)_(n)—C(═O)— (n=1to 4), —CH═CH— (CH₂)_(n)— (n=0 to4), —C≡C—(CH₂)_(n) (n=0 to 4), —CH₂—O—, —CH₂—S—, —(CH₂)₂—O—CH₂—, or—CH═CH—CH═CH—(CH₂)n- (n=O to 4), and more preferably a straight-chainalkylene group having from 1 to 3 carbon atoms, —CH═CH—, —C≡C—, —CH₂—O—or —CH₂—S—, with a straight-chain alkylene group having from 1 to 3carbon atoms, —CH═CH—, or —C≡C— being most preferable.

R⁵ is preferably a hydrogen atom or an organic group having any one ofthe following fundamental structures:

Organic Groups Represented by R⁵

wherein the organic group may be substituted by a substituents selectedfrom the group consisting of an alkyl group having from 1 to 5 carbonatoms, an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxygroup having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom,a chlorine atom, a bromine atom, an amino group, a nitro group, a cyanogroup, a isothiocyanato group, a trifluoromethyl group, atrifluoromethoxygroup, and a methylenedioxy group. Among them, ahydrogen atom, a phenyl group, 4-methylphenyl, 3-methylphenyl,2-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl,3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 4-hydroxyphenyl,3-hydroxyphenyl, 3,4-dihydroxyphenyl, 4-fluorophenyl, 3-fluorophenyl,2-fluorophenyl, 3,4-difluorophenyl, perfluorophenyl, 4-chlorophenyl,3-chlorophenyl, 2-chlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl,2,4,5-trichlorqphenyl, 2,4,6-trichlorophenyl, 4-bromophenyl,3-bromophenyl, 2-bromophenyl, 4-nitrophenyl, 3-nitrophenyl,2-nitrophenyl, 4-aminophenyl, 3-aminophenyl, 2-aminophenyl,4-trifluoromethylphenyl, 3-trifluoromethylphenyl,2-trifluoromethylphenyl, 4-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl,3,4-methylenedioxyphenyl, 3-furanyl, 2-furanyl, 3-thienyl, 2-thienyl,cyclopentyl or cyclohexyl are particularly preferred. Of course R⁵ isnot limited to these. These opiate κ receptor agonists represented bythe general formula (I) can be produced, for example, by the methoddisclosed in Japanese Patent No.2525552.

Among the κ receptor agonists in accordance with the present inventionrepresented by the general formula (II), preferred aretrans-2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]acetamide; trans-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl] benzo [b]thiophene-4-acetamide; (5β, 7β,8α)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1 -oxaspiro [4,5]dec-8-yl] benzeneacetamide; (5β, 7β,8α)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro [4,5] dec-8-yl] benzo [b]furan-4-acetamide; and (5β, 7β,8α)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro [4,5] dec-8-yl]benzeneacetamide. The κ receptor agonists represented by the generalformula (II) can be produced, for example, by the methods according toSzmuszkovicz, J. et al., J. Med. Chem., 25, 1125 (1982); Horwell, D. C.,et al., U.S. Patent Appl., 558737 (1983); Szmuszkovicz, J. et al., Eur.Patent Appl., EP126612 (1984); Halfpenny, P. R., et al., J. Med. Chem.,33, 286 (1990); or the like.

Among the κ receptor agonists in accordance with the present inventionrepresented by the general formula (III), preferred are methyl4-[(3,4-dichlorophenyl) acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate; 1-[(4-trifluoromethylphenyl)acetyl]-2-[(1-pyrrolidinyl) methyl] piperidine; 1-[(3,4-dichlorophenyl)acetyl]-2-[(1-pyrrolidinyl) methyl] piperidine; and1-[(3,4-dichlorophenyl) acetyl]-4,4-ethylenedioxy-2[(1-pyrrolidinyl)methyl] piperidine. The κ receptor agonists represented by the generalformula (III) can be produced by the methods according to Naylor, A., etal., J. Med. Chem., 36, 2075 (1993); Vecchietti, V., et al., J. Med.Chem., 34, 397 (1991); Eur. Patent Appl. EP232612 (1987), EP260041(1988), EP275696 (1988); Scopes, D.I.C., et al., J. Med. Chem., 35, 409(1992) or the like.

Among the κ receptor agonists in accordance with the present inventionrepresented by the general formula (IV), preferred are3-(1-pyrrolidinylmethyl)-4-[5,6-dichloro-1-indanecarbonyl]-tetrahydro-1,4-thiazine.These κ receptor agonists represented by the general formula (IV) can beproduced, for example, by the method disclosed in WO 94/05646.

Among the κ receptor agonists in accordance with the present inventionrepresented by the general formula (V), preferred are2-(3,4-dichlorophenyl)-N-methyl-N-[1-phenyl-2 -(1-pyrrodinyl) ethyl]acetamide. These κ receptor agonists represented by the general formula(V) can be produced, for example, by the method according to Barlow, J.J., et al., J. Med. Chem., 34, 3149(1991).

Among the pharmacologically acceptable acid-addition salts of the opioidκ receptor agonists described above are inorganic acid salts, such ashydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides, andphosphates; organic carboxylates, such as acetates, lactates, citrates,oxalates, glutarates, malates, tartrates, fumarates, mandelates,maleates, benzoates, and phthalates; and organic sulfonates, such asmethanesulfonates, ethanesulfonates, benzenesulfonates,p-toluenesulfonates, and camphorsulfonates. Among them, hydrochlorides,hydrobromides, phosphates, tartrates, and methanesulfonates arepreferred, but of course they are not limited to those compounds.

The opioid κ receptor agonists in accordance with the present inventioninhibit dopamine release from the dopamine nervous system in themesolimbic system which projects from a ventral tagmental area to thenucleus accumbens, so that they are useful as dopamine-releaseinhibitors. Dopamine is closely related with drug dependence.Dependence-producing drugs such as cocaine; opioid μ agonists; nicotine;alcohol; stimulants; central nervous system sedatives, for example,barbiturates, benzodiazepines, and the like; and hallucinogens induce areward effect due to an increase in dopamine release from the dopaminenervous system in the mesolimbic system, so that the onset of drugdependence is triggered. Therefore, the opioid κ receptor agonists inaccordance with the present invention are useful for treating drugdependence induced by drugs which facilitate dopamine release.

The drug dependence dealt by the present invention represents psychicdependence and physical dependence induced by dependence-producingdrugs. Examples of the diseases which can be treated by the remedy inaccordance with the present invention are cocaine dependence, opioid μreceptor agonist dependence, nicotine (tobacco) dependence, alcoholdependence, stimulant dependence, central nervous system sedativedependence, and hallcinogen dependence.

Examples of drugs which induce the above-mentioned drug dependences areopioid μ receptor agonists such as morphine, heroin, and codeine;stimulants such as amphetamine and methamphetamine; central nervoussystem sedatives such as the barbiturates, for example, phenobarbital,pentobarbital, thiopental, and the like, and the benzodiazepines, forexample, diazepam, lorazepam, oxazepam, chlordiazepoxide, and the like;and hallucinogens such as phencyclidine. Of course, however, they arenot limited to those compounds.

Therapeutic effects of the opioid κ receptor agonists in accordance withthe present invention against drug dependence can be assessed by aconditioned place preference method (a CPP method) and a drugdiscrimination test which are used for assessing psychic dependence,assessment a withdrawal syndrome due to administration of an antagonistwhich is used as a method for assessing physical dependence, or the like(Suzuki, T. et al., Psychopharmacology, 102, 438-442 (1990); Spyraki,C., The psychopharmacology of dependence, p96, Oxford MedicalPublications, New York (1988); Yanagita, T., Psychopharmacology, 27, 503(1975); Deueau, G. A. et al., Psychopharmacology, 16, 30 (1969); TsutomuSuzuki, Molecular Medicine, 32, 140 (1995); Maldonado, R. et al., J.Pharmacol. Exp. Ther., 261, 669 (1992)). A significant inhibitory effecton psychic dependence and physical dependence has been confirmed bythese tests.

After the opioid κ receptor agonists in accordance with the presentinvention have been purified to yield a purity which is appropriate formedical use and have passed the required safety tests, they can beorally or parenterally administered without additives or as medicalcompositions including known pharmacologically acceptable acids,carriers, vehicles, and the like.

With respect to parenterally administrated composition, the compounds inaccordance with the present invention can be administered using a liquidcarrier such as sterilized water without pyrogens, sterilized ethyloleate without peroxides, anhydrous alcohol, polypropylene glycol, andmixtures thereof, which can be usually used for injection.

Pharmaceutical adjuvants suitable for an injection solution can includestabilizers, solubilizers, buffers, viscosity modifiers, andantioxidants. Examples of these adjuvants are ethanol,ethylenediaminetetraacetic acid (EDTA), tartrate buffers, citratebuffers, and polyethylene oxide viscosity modifiers. Thesepharmaceutical preparations can be intramuscularly, intraperitoneally,or intravenously injected.

The compounds in accordance with the present invention can be orallyadministered as solid or liquid pharmaceutical compositions accompaniedwith a conventional solid or liquid compatible carrier. Thepharmaceutical composition which is orally administered can includebinders such as syrups, acacia gum, gelatin, sorbitol, tragacanth gum,polyvinyl pyrrolidone, or mixtures thereof, that is, conventionalingredients may be used,

Furthermore, the composition can include fillers such as lactose,mannitol, starch, calcium phosphate, sorbitol, methyl cellulose, ormixtures thereof.

In addition, the orally administrated composition can include lubricantssuch as magnesium stearate, high molecular weight polymers such aspolyethylene glycol, high molecular weight fatty acids such as stearicacid, silica or additives such as starch, which facilitatedisintegration of solid pharmaceutical preparations, and lubricants suchas sulfuric acid lauryl sodium.

The orally administrated composition can be prepared as any conventionalforms such as tablets, capsules, lozenges, aqueous or oil suspensions,emulsions, or powders which can be reconstituted using water or otherproper solutions before use.

Solid or liquid constituents can include flavors, sweeteners and/orpreservatives such as alkyl p-hydroxy benzoate. The liquid constituentscan, furthermore, include suspensions such as sorbitol, glucose, othersugar syrups, methyl cellulose, hydroxymethyl cellulose, carboxymethylcellulose, or gelatin; emulsifiers such as lecithin or sorbitolmonooleate; or a usual thickening agent. The liquid constitutents canbe, for example, encapsulated in a gelatin capsule.

The pharmaceutical composition in accordance with the present inventionis most preferably available in units. In the above-mentionedconstitution, the pharmaceutical preparation is subdivided into unitdosages having an adequate dose of an active ingredient. A availableunit constitution can be prepared as a packaged pharmaceuticalpreparation having a package which includes a non-homogenized dose ofthe pharmaceutical preparation. The package may have constitution suchas tablets, capsules, powders, vials, or ampoules. The available unitconstitution may be capsules, cachets, tablets, pharmaceuticalcomposition as such, or optionally and properly packaged constitutionthereof.

The dosage is properly selected according to symptoms, age, body weight,and administration route. In adults, the daily dosage ranges from 0.001mg to 1 g as an active ingredient, when it is injected, and the dailydosage ranges from 0.005 mg to 3 g, when it is orally administered. Ineach case, the dosage can be administered once a day or several times aday.

EXAMPLES

The present invention is described in further detail below withreference to examples.

Example 1

Inhibitory effects of opioid κ receptor agonists against development ofpsychic dependence induced by an opioid μ receptor agonist.

Inhibitory effects of the opioid κ receptor agonists against developmentof psychic dependence induced by an opioid μ receptor agonist wereexamined by a conditioned place preference method (Suzuki, T. et al.,Psychopharmacology, 102, 438-442 (1990); Spyraki, C., Thepsychopharmacology of dependence, p96, Oxford Medical Publications, NewYork (1988); hereinafter referred to as a CPP method). Morphine was usedas the opioid μ receptor agonist which developed psychic dependence. Onthe other hand,17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-3-(4-trifluoromethylphenyl)propiolamide]morphinan maleate (Compound 1) and17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-(N-methyl-3-methylcinnamide)morphinan hydrochloride (Compound 2) were used as the opioid κ receptorselective agonists.

Animals used were Sprague Dawley strain (SD strain) male rats in thisexperiment. Experiments used were CPP operant boxes having twocompartments colored white and black, respectively. In this experiment,animals were given conditioning training for a sensation effect on adrug and environments in the operant boxes (white and black) for sixdays. After the period for the conditioning training, tests were carriedout by placing the conditioned animals in the operant boxes withoutadministration of the drug. Drug dependence and drug aversion wereassessed from the periods in which the rats remained in the white orblack box during the test.

Accordingly, as shown in FIGS. 1 and 2, the periods, in which the ratsremained in the box conditioned by the drug, with administration ofmorphine alone (3 mg/kg, subcutaneously administration) wassignificantly prolonged compared with a control group to which thesolvent was administered. Therefore, development of dependence wasrecognized. In contrast, it was recognized that the periods in which therats remained was not significantly prolonged in the test groups whichwere given morphine in combination with Compound 1 or Compound 2compared with the control group. Therefore, it was clear that Compound 1and Compound 2 inhibited the development of drug dependence caused bymorphine, when they were subcutaneously given 0.1 mg/kg, respectively.In addition, it was recognized that the periods in which the ratsremained of the group given Compound 1 alone or that of Compound 2 alonewas not prolonged both in the drug-conditioned box and in thesolvent-conditioned box compared with the control group to which thesolvent was administered. Therefore, it was clear that these compoundsdid not develop psychic dependence and aversion.

In addition, in FIGS. 1 and 2, a symbol * represents a level ofsignificance of not more than 5%, thereby indicating statisticalsignificance.

Example 2

Inhibitory effects of an opioid κ receptor agonist against developmentof psychic dependence induced by an opioid μ receptor agonist, and aresult of an antagonism test on an opioid κ receptor antagonist.

Inhibitory effects of the opioid κ receptor agonist against developmentof psychic dependence induced by an opioid μ receptor agonist wereexamined by a CPP method (Suzuki, T. et al., Psychopharmacology, 102,438-442 (1990); Spyraki, C., The psychopharmacology of dependence, p96,Oxford Medical Publications, New York (1988)). Morphine was used as theoploid μ receptor agonist which developed psychic dependence. On theother hand,17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride (Compound 3) was used as the opioid κ receptorselective agonist. The same experimental procedure was performed as thatin Example 1.

Accordingly, as shown in FIG. 3, the periods in which the rats remainedin the box conditioned by the drug was significantly prolonged due tothe administration of morphine alone (5 mg/kg, subcutaneouslyadministration). Therefore, development of dependence was recognized. Incontrast, it was recognized that the periods in which the rats remainedwas significantly reduced in the test groups which were given morphinein combination with Compound 3 compared with the group to which morphinealone was administered. Therefore, it was clear that Compound 3inhibited the development of drug dependence caused by morphine, whenthey were subcutaneously given 0.01 or 0.03 mg/kg of Compound 3,respectively. Furthermore, the inhibitory effect caused by Compound 3was significantly antagonized by pretreatment with norbinaltorphimine(nor-BNI) (3 mg/kg), that is, an opioid κ receptor selective antagonist,so that it was clear that the inhibitory effect caused by Compound 3 ondrug dependence was mediated by the opioid κ receptor.

In addition, it was recognized that the periods in which the ratsremained in the group given Compound 3 alone was not prolonged both inthe drug-conditioned box and in the solvent-conditioned box comparedwith the control group to which the solvent was administered. Therefore,it was clear that the Compound 3 did not produce psychic dependence andaversion.

In FIG. 3, a symbol * represents a level of significance of not morethan 5%, and a symbol ** represents a level of significance of not morethan 1% with respect to the morphine alone treated group (5 mg/kg,subcutaneously administration), thereby indicating statisticalsignificance. Furthermore, a symbol ## represents a level ofsignificance of not more than 1% with respect to the morphine (5 mg/kg,subcutaneously administration) in combination with Compound 3 (0.03mg/kg, subcutaneously administration) treated group, thereby indicatingstatistical significance.

Example 3

Effects of an opioid κ receptor agonist on a naloxone-induced withdrawalsyndrome (a weight reduction).

Inhibitory effects of the opioid κ receptor agonist on development ofphysical dependence induced by an opioid μ receptor agonist wereexamined (Tsutomu Suzuki, Molecular Medicine, 32, 140 (1995); Maldonado,R. et al., J. Pharmacol. Exp. Ther., 261, 669 (1992)). Morphine was usedas the opioid μ receptor agonist which developed physical dependence. Onthe other hand,17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide] morphinan hydrochloride (Compound 3) was used as theopioid κ receptor selective agonist.

Animals used were ddY strain male mouse. Physical dependence wasdeveloped using an injection method. Morphine was repeatedly andsubcutaneously administered to the mouse twice a day for five days at adose ranging from 8 to 45 mg/kg, the dose being gradually increased.Naloxone (3 mg/kg) was subcutaneously administered two hours after thelast administration of morphine. Then, just after the administration ofnaloxone, a withdrawal syndrome was observed for 60 minutes. Compound 3was simultaneously administered with morphine.

Accordingly, as shown in FIG. 4 and Table 1, the withdrawal syndrome wasrecognized in the mouse, to which morphine alone was administered,because of the naloxone administration. Therefore, it was confirmed thatphysical dependence-was developed by morphine. The withdrawal syndromewas relieved by the simultaneous administration of Compound 3 in adose-dependent manner. Incidence rates of jumping, shaking, and diarrheawere significantly decreased by administration of Compound 3 at a doseof 0.03 mg/kg compared with the group to which morphine alone wasadministered. In addition, it was recognized that both Compound 3 groupsadministered at a dose of 0.01 or 0.03 mg/kg revealed significantsuppression of body weight reduction compared with the morphine aloneadministered group. This result showed that the opioid κ receptoragonist inhibited development of physical dependence induced by theopioid p receptor agonist.

TABLE 1 Effects of an opioid κ receptor agonist on a withdrawalsyndromeinduced by naloxone Numbers of mouse manifesting withdrawal syndrome/Numbers of total mouse Withdrawal Physiological Compound 3 (mg/kg, s.c.)syndrome saline 0.003 0.01 0.03 Jumping 10/10  3/10  5/10  3/10*Wobbling 10/10  7/10  5/10  3/10* Rearing 10/10 10/10  7/10  8/10Diarrhea 10/10  7/10  6/10  3/10* Blepharoptosis 10/10 10/10 10/10 10/10Fore paw tremor 10/10  9/10 10/10  7/10

In FIG. 4, a symbol  represents the group which was given morphinealone, a symbol ◯ represents the group which was given morphine incombination with Compound 3 (0.003 mg/kg, subcutaneouslyadministration), a symbol Δ represents the group which was givenmorphine in combination with Compound 3 (0.01 mg/kg, subcutaneouslyadministration), and a symbol □ represents the group which was givenmorphine in combination with Compound 3 (0.03 mg/kg, subcutaneouslyadministration). A symbol * represents a level of significance of notmore than 5%, thereby indicating statistical significance.

Example 4

Inhibitory effects of opioid κ receptor agonists on development ofpsychic dependence induced by cocaine.

Inhibitory effects of the opioid κ receptor agonists on development ofpsychic dependence induced by cocaine were examined by a CPP method(Suzuki, T. et al., Psychopharmacology, 102, 438-442 (1990); Spyraki,C., The psychopharmacology of dependence, p96, Oxford MedicalPublications, New York (1988)).17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-3-(3-methylphenyl)propiolamide]morphinan hydrochloride (Compound 4) and17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(methoxycinnamide)morphinan tartrate (Compound 5) were used as the opioid κ receptorselective agonists.

Animals used were Sprague Dawley strain (SD strain) male rats in thisexperiment. Experiments used were CPP operant boxes having twocompartments colored white and black, respectively. In this experiment,animals were given conditioning training for a sensation effect on adrug and environments in the operant boxes (white and black) for sixdays. After the period for the conditioning training, tests were carriedout by placing the conditioned animals in the operant boxes withoutadministration of the drug. Drug dependence and drug aversion wereassessed from the periods in which the rats remained in the white orblack box during the test.

Accordingly, as shown in FIGS. 5 and 6, the periods, in which the ratsremained in the box conditioned by the drug, in the group administeredcocaine alone (10 mg/kg, intraperitoneal administration) wassignificantly prolonged compared with that in a control group to whichthe solvent was administered. Therefore, development of dependence wasrecognized. In contrast, it was recognized that the periods in which therats remained was not significantly prolonged in the test groups whichwere given cocaine in combination with Compound 4 or Compound 5 comparedwith that in the control group which was given solvent. Therefore, itwas clear that Compound 4 and Compound 5 inhibited the development ofdrug dependence induced by cocaine, when they were subcutaneously given0.1 mg/kg of Compound 4 and Compound 5, respectively. In addition, itwas recognized that the periods in which the rats remained in the groupgiven Compound 4 alone or that of Compound 5 alone was not prolongedboth in the drug-conditioned box and in the solvent-conditioned box.Therefore, it was clear that these compounds did not produce psychicdependence and aversion.

In addition, in FIGS. 5 and 6, a symbol * represents a level ofsignificance of not more than 5%, thereby indicating statisticalsignificance.

Example 5

Inhibitory effects of an opioid κ receptor agonist on development ofpsychic dependence induced by cocaine.

Inhibitory effects of the opioid κ receptor agonist on development ofpsychic dependence induced by cocaine was examined by a CPP method(Suzuki, T. et al., Psychopharmacology, 102, 438-442 (1990); Spyraki,C., The psychopharmacology of dependence, p96, Oxford MedicalPublications, New York (1988)).17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-3-(4-trifluoromethylphenyl)propiolamide]morphinan maleate (Compound 1) was used as the opioid κ receptorselective agonist. The same experimental procedure was performed as thatin Example 4.

Accordingly, as shown in FIG. 7, the periods, in which the rats remainedin the box conditioned by the drug, in the group administered cocainealone (4 mg/kg, intraperitoneal administration) was significantlyprolonged, so that development of dependence was recognized. Incontrast, it was recognized that the period in which the animalsremained was significantly decreased in the test group which were givencocaine in combination with Compound 1 compared with that in the controlgroup which was given cocaine alone. Therefore, it was clear thatCompound 1 inhibited the development of drug dependence induced bycocaine, when it was intraperitoneally given 0.2 mg/kg.

In addition, it was recognized that the period in which the ratsremained in the group given Compound 1 alone was not prolonged both inthe drug-conditioned box and in the solvent-conditioned box comparedwith that in the control group which was given solvent. Therefore, itwas clear that the compound did not produce psychic dependence andaversion.

In addition, in FIG. 7, a symbol ** represents a level of significanceof not more than 1%, thereby indicating statistical significance.

Example 6

Inhibitory effect of opioid κ receptor agonist on a drug discriminationtest.

Rats were preliminarily trained for the drug discrimination test(Yanagita, T., Psychopharmacology, 27, 503 (1975); Deueau, G. A. et al.,Psychopharmacology, 16, 30 (1969)) by previously giving cocaine at adose of 10 mg/kg or physiological saline, in which an indicator isfeeding behavior with lever pressing.17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride (Compound 3), that, is, an opioid κ receptorselective agonist (10 μg/kg) was administered in combination withcocaine (each dose) to the rats, so that the drug discrimination testwas performed.

The results are shown in FIG. 8. Rates of feeding behavior with leverpressing were significantly decreased in the groups which wereadministered cocaine at a dose of 1.25, 2.5, or 5 mg/kg in combinationwith Compound 3 compared with that in the solvent control group whichwas administered cocaine in combination with physiological saline.Accordingly, it was revealed that Compound 3 inhibited manifestation ofa reward effect induced by cocaine, so that Compound 3 is suggested tobe a promising remedy for cocaine dependence.

In FIG. 8, a symbol  represents the group which was given physiologicalsaline in combination with cocaine, and a symbol ◯ represents the groupwhich was given Compound 3 (0.01 mg/kg) in combination with cocaine. Asymbol * represents a level of significance of not more than 5%, therebyindicating statistical significance.

Furthermore, it was clear that when Compound 3 (20 μg/kg) was given incombination with cocaine (each dose), inhibitory effect of cocainediscrimination was enhanced compared with the case in which Compound 3(10 μg/kg) was given. In addition, as shown in FIG. 9, when nor-BNI,that is, an opioid κ receptor antagonist was pretreated, rates offeeding behavior with lever pressing were same as those in the groupgiven physiological saline in combination with cocaine. Thus, theinhibitory effect of cocaine discrimination of Compound 3 wasantagonized by the opioid κ receptor antagonist. These results showedthat the inhibitory effect of cocaine discrimination was manifested viathe opioid κ receptor, so that psychic dependence induced by cocainecould be inhibited by the opioid κ receptor agonist.

In FIG. 9, a symbol  represents the group which was given physiologicalsaline in combination with cocaine, a symbol ◯ represents the groupwhich was given Compound 3 (0.02 mg/kg) in combination with cocaine, anda symbol □ represents the group which was given Compound 3 (0.02 mg/kg)in combination with cocaine after the pretreatment of nor-BNI. A symbol** represents a level of significance of not more than 1%, therebyindicating statistical significance.

Example 7

Inhibitory effects on a mecamylamine-induced nicotine withdrawalsyndrome by an opioid κ receptor agonist

Animals used were SD strain male rats in this experiment. Experimentsused were CPP operant boxes. Experiments were performed by using anaversive model in a nicotine withdrawal syndrome induced bymecamylamine, that is, a nicotine receptor antagonist. (Tsutomu Suzuki,Molecular Medicine, 32, 140 (1995); Suzuki, T. et al., Eur. J. Pharm.,314, 281 (1996); Maldonado, R. et al., J. Pharmacol. Exp. Ther., 261,669 (1992)). Osmotic minipump (Alzet 2001, Alza Corporation) injectedwith nicotine (1 μl/hr, for seven days) was implanted under dorsal skinof the rats. An aqueous solution at a concentration of 121.4 mg/ ml wasprepared so that a nicotine dose was adjusted to 10 mg/kg/day. Then, theaqueous solution was filled into the osmotic minipump. The rats weregiven conditioning training by the following counter-balance method. Inthe morning of the seventh day after the implantation of themini-osmotic pump, mecamylamine (1 mg/ml), that is, nicotine receptorantagonist or physiological saline was subcutaneously injected. Then,the rats were placed in one compartment for 60 minutes. And then, in theevening of the same day, the opposite treatments were performed(physiological saline was administered to the rats to which mecamylaminehad been administered in the morning, and mecamylamine was administeredto the rats to which physiological saline was administered in themorning), and the rats were placed in the other compartment for 60minutes. Then,17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride (Compound 3), that is, an opioid κ receptorselective agonist was subcutaneously administered 30 minutes before themecamylamine treatment. On the next day of the conditioning training(the eighth day), tests were performed. The periods in which the ratsremained in each compartment colored white or black were measured for 15minutes.

The results were shown in FIG. 10. A negative value indicates the periodin which rats escaped from the compartment conditioned by sucutaneousinjection of mecamylamine. It was shown that the greater the negativevalue means the stronger the aversive effect at the nicotine withdrawal.The aversive effect induced by mecamylamine was inhibited by thepretreatment with Compound 3 (10 or 30 μg/kg) in a dose dependentmanner. In addition, it was recognized that the pretreatment of Compound3 (30 μg/kg) significantly inhibited the aversive effect compared withthe aversive effect in the group pretreated with physiological saline.That is, the physical dependence developed by nicotine was inhibited.

In FIG. 10, a symbol * represents a level of significance of not morethan 5%, thereby indicating statistical significance.

Example 8

Inhibitory effects on dopamine release by an opioid κ receptor agonist.

Animals used were SD strain male rats at an age of at least six weeks.After rats were killed by decapitation, the forebrains were enucleated.The forebrains were longitudinally severed in the mediad direction inKrebs-Ringer-Bicarbonate medium which were chilled in cracked ice, andsliced with a tissue chopper at intervals of 500 μm. The nucleusaccumbens areas were knocked through the slices containing the nucleusaccumbens using a punch having an inner diameter of 2 mm. After thenucleus accumbens were preincubated in the Krebs-Ringer-Bicarbonatemedium under bubbling a gas containing O₂ at 95% and CO₂ at 5% for 20minutes, they were placed in a reflux apparatus so as to be 24 slicesper a chamber, and refluxed with the Krebs-Ringer-Bicarbonate mediumwhich were added with nomifensine at a concentration of 10 μM for 30minutes. Then, the reflux was performed at a rate of 0.25 ml/min. andsamples were obtained at intervals of five minutes. After 20 minutes,and 60 minutes, 20 mM high K⁺ stimulation were subjected for 10 minutesso as to facilitate dopanime release. 17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride (Compound 3), that is, an opioid κ receptoragonist was dissolved in distilled water, diluted with the medium, andadded 20 minutes before the second stimulus. The amounts of dopamine inthe recovered samples were measured using a high-performance liquidchromatography-electron capture detector (HPLC-ECD) method at a flowrate of 0.25 ml/min, at a column temperature of 25° C., and at anapplied voltage of 400 mV, in which a mobile phase was 0.1 M phosphatebuffer (pH 6.0) and a Eicompak CA-50DS column (2.1φ×150 mm) attached bya precolumn was used.

The results were shown in FIG. 11. It was suggested that Compound 3inhibited dopamine release in the nucleus accumbens projected form A10nerve terminals which related to a drug reward effect.

Referring to FIG. 11, a symbol * represents a level of significance ofnot more than 5% and a symbol ** represents a level of significance ofnot more than 1%, thereby indicating statistical significance.

INDUSTRIAL APPLICABILITY

A remedy for drug dependence in accordance with the present invention isa promising medicament with reduced adverse effects, which inhibitsdevelopment of psychic dependence, and also physical dependence byinhibiting reward effects induced by dependence-producing drugs.

What is claimed is:
 1. A method for treating nicotine dependence,alcohol dependence, stimulant dependence, central nervous systemsedative dependence, or hallucinogen dependence, which method comprisesadministering to a patient an opioid k receptor agonist represented bythe following formula (I) or a pharmacologically acceptableacid-addition salt thereof:

wherein

is a double bond, or a single bond; R¹ is an alkyl group having from 1to 5 carbon atoms, a cycloalkylalkyl group having from 4 to 7 carbonatoms, a cycloalkenylalkyl group having from 5 to 7 carbon atoms, anaryl group having from 6 to 12 carbon atoms, an aralkyl group havingfrom 7 to 13 carbon atoms, an alkenyl group having from 4 to 7 carbonatoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5 carbonatoms, or a thiophen-2-ylalkyl group having from 1 to 5 carbon atoms; R²is a hydrogen atom, a hydroxy group, a nitro group, an alkanoyloxy grouphaving from 1 to 5 carbon atoms, an alkoxy group having from 1 to 5carbon atoms, an alkyl group having from 1 to 5 carbon atoms, or−NR⁹R¹⁰; R⁹ is a hydrogen atom or an alkyl group having from 1 to 5carbon atoms; R¹⁰ is a hydrogen atom, an alkyl group having from 1 to 5carbon atoms, or —C(═O)R¹¹ is a hydrogen atom, a phenyl group, or analkyl group having from 1 to 5 carbon atoms; R³ is a hydrogen atom, ahydroxy group, an alkanoyloxy group having from 1 to 5 carbon atoms, oran alkoxy group having from 1 to 5 carbon atoms; A is —XC(═Y)—,—XC(═Y)Z—, —X—, or —XSO₂, wherein X, Y and Z are, independently of oneanother, NR⁴, S, or O; and R⁴ is a hydrogen atom, a straight-chain orbranched-chain alkyl group having from 1 to 5 carbon atoms, or an arylgroup having from 6 to 12 carbon atoms; and R⁴ is optionally identicalor different in the formula; B is a valence bond, a straight-chain orbranched-chain alkylene group having from 1 to 14 carbon atoms, whereinthe alkylene group is optionally substituted by one or more substituentsselected from the group consisting of an alkoxy group having from 1 to 5carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, ahydroxy group, a fluorine atom, a chlorine atom, a bromine atom, aniodine atom, an amino group, a nitro group, a cyano group, atrifluoromethyl group, a trifluoromethoxy group, and a phenoxy group,and wherein one to three methylene groups of the alkylene group isoptionally replaced with carbonyl groups, a straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds and having from 2 to 14 carbonatoms, wherein the acyclic unsaturated hydrocarbon is optionallysubstituted by one or more substituents selected from the groupconsisting of an alkoxy group having from 1 to 5 carbon atoms, a hydroxygroup, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom,an amino group, a nitro group, a cyano group, a trifluoromethyl group, atrifluoromethoxy group, and a phenoxy group, and wherein one to threemethylene groups of the acyclic unsaturated hydrocarbon is optionallyreplaced with carbonyl groups, or a straight-chain or branched-chainsaturated or unsaturated hydrocarbon containing from one to fivethioether, ether, and/or amino bonds and having from 1 to 14 carbonatoms, wherein no hetero atoms are bonded directly to A, and one tothree methylene groups of the hydrocarbon is optionally replaced withcarbonyl groups; and R⁵ is a hydrogen atom or an organic group having abasic skeleton selected from the group consisting of the followingformulas:

wherein the organic group optionally has at least one substituentselected form the group consisting of an alkyl group having from 1 to 5carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aminogroup, a nitro group, a cyano group, an isothiocyanate group, atrifluoromethyl group, a trifluoromethoxy group, and a methylenedioxygroup; R⁶ is a hydrogen atom; R⁷ is a hydrogen atom, a hydroxy group, analkoxy group having from 1 to 5 carbon atoms, or R⁶ and R⁷ are —O—,—CH₂—, —S— together; R⁸ is a hydrogen atom, an alkyl group having from 1to 5 carbon atoms or an alkanoyl group having from 1 to 5 carbon atoms.2. The method for treating nicotine dependence of claim 1, wherein inthe formula (I), R¹ is a methyl group, an ethyl group, a propyl group, abutyl group, an isobutyl group, a cyclopropylmethyl group, an allylgroup, a benzyl group, or a phenethyl group; R² and R³ are,independently of each other, a hydrogen atom, a hydroxy group, anacetoxy group, or a methoxy group; A is —XC(═Y)—, wherein X is NR⁴, S,or O; Y is O; and R⁴ is a hydrogen atom, or a straight-chain orbranched-chain alkyl group having from 1 to 5 carbon atoms, —XC(═Y)Z—,—X—, or —XSO₂, wherein X is NR⁴; Y is O or S; Z is NR⁴or O; and R⁴ is ahydrogen atom, or a straight-chain or branched-chain alkyl group havingfrom 1 to 5 carbon atoms; B is a straight-chain alkylene group havingfrom 1 to 3 carbon atoms, —CH═CH—, —C═C—, —CH₂O— or —CH₂S—; R⁵ is asdefined in claim 1; R⁶ and R⁷ are —O— together; and R⁸ is a hydrogenatom.
 3. The method for treating nicotine dependence of claim 2, whereinin the formula (I), A is —NR-4-C(═O)— or —NR—⁴C(═O)O—, wherein R-4- is ahydrogen atom, or a straight-chain or branched-chain alkyl group havingfrom 1 to 5 carbon atoms; B is a straight-chain alkylene group havingfrom 1 to 3 carbon atoms, —CHαCH—, or —C═C—; and R⁵ is a hydrogen atomor an organic group having a basic skeleton selected from the groupconsisting of the following formulas:

wherein the organic group optionally has at least one substituentselected from the group consisting of an alkyl group having from 1 to 5carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, ahydroxy group, a fluorine atom, a chlorine atom, a bromine atom, aniodine atom, an amino group, a nitro group, a cyano group, anisothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group,and a methylenedioxy group.
 4. A method for treating cocaine dependencewhich comprises administering an opioid k receptor agonist, or apharmacologically acceptable acid-addition salt thereof, to a patientwho is dependent on cocaine, wherein said opioid k receptor agonist isrepresented by the following formula (I):

wherein

is a double bond, or a single bond; R¹is an alkyl group having from 1 to5 carbon atoms, a cycloalkylalkyl group having from 4 to 7 carbon atoms,a cycloalkenylalkyl group having from 5 to 7 carbon atoms, an aryl grouphaving from 6 to 12 carbon atoms, an aralkyl group having from 7 to 13carbon atoms, an alkenyl group having from 4 to 7 carbon atoms, an allylgroup, a furan-2-ylalkyl group having from 1 to 5 carbon atoms, or athiophen-2-ylalkyl group having from 1 to 5 carbon atoms; R² is ahydrogen atom, a hydroxy group, a nitro group, an alkanoyloxy grouphaving from 1 to 5 carbon atoms, an alkoxy group having from 1 to 5carbon atoms, or —NR⁹R¹⁰; R⁹ is a hydrogen atom or an alkyl group havingfrom 1 to 5 carbon atoms; R¹⁰ is a hydrogen atom, an alkyl group havingfrom 1 to 5 carbon atoms; R³ is a hydrogen atom, a hydroxy group, analkanoyloxy group having from 1 to 5 carbon atoms, or an alkoxy grouphaving from 1 to 5 carbon atoms; A is —XC(═Y)—, —XC(═Y)Z—, —X—, or—XSO², wherein X, Y and Z are, independently of one another, NR⁴S, or O;and R⁴ is a hydrogen atom, a straight-chain or branched-chain alkylgroup having from 1 to 5 carbon atoms; and R⁴ is optionally identical ordifferent in the formula; B is a valence bond, a straight-chain orbranched-chain alkylene group having from 1 to 14 carbon atoms, whereinthe alkylene group is optionally substituted by one or more substituentsselected from the group consisting of an alkoxy group having from 1 to 5carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, ahydroxy group, a fluorine atom, a chlorine atom, a bromine atom, aniodine atom, an amino group, a nitro group, a cyano group, atrifluoromethyl group, a trifluoromethoxy group, ad a phenoxy group, andwherein one to three methylene groups of the alkylene group isoptionally replaced with carbonyl groups, straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds and having from 2 to 14 carbonatoms, wherein the acyclic unsaturated hydrocarbon is optionallysubstituted by one or more substituents selected from the groupconsisting of an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aminogroup, a nitro group, a cyano group, a trifluoromethyl group, atrifluoromethoxy group, and a phenoxy group, and wherein one to threemethylene groups of the acyclic unsaturated hydrocarbon is optionallyreplaced with carbonyl groups, or a straight-chain or branched-chainsaturated or unsaturated hydrocarbon containing from one to fivethioether, ether, and/or amino bonds and having from 1 to 14 carbonatoms, wherein no hetero atoms are bonded directly to A, and one tothree methylene groups of the hydrocarbon is optionally replaced withcarbonyl groups; and R⁵ is a hydrogen atom or an organic group having abasic skeleton selected from the group consisting of the followingformulas:

wherein the organic group optionally has at least one substituentselected from the group consisting of an alkyl group having from 1 to 5carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, a hydroxygroup, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom,an amino group, a nitro group, a cyano group, an isothiocyanate group, atrifluoromethyl group, a trifluoromethoxy group, and a methylenedioxygroup; R⁶ is a hydrogen atom; R⁷ is a hydrogen atom, a hydroxy group, analkoxy group having from 1 to 5 carbon atoms, or an alkanoyloxy grouphaving from 1 to 5 carbon atoms, or R⁶ and R⁷ are —O—, —CH₂—, —S—together; R⁸ is a hydrogen atom, an alkyl group having from 1 to 5carbon atoms or an alkanoyl group having from 1 to 5 carbon atoms. 5.The method for treating cocaine dependence of claim 4, wherein in thegeneral formula (I), R¹ is a methyl group, an ethyl group, a propylgroup, a butyl group, an isobutyl group, a cyclopropylmethyl group, anallyl group, a benzyl group, or a phenethyl group; R² and R³ are,independently of each other, a hydrogen atom, a hydroxy group, anacetoxy group, or a methoxy group; A is —XC(═Y)—, wherein X is NR⁴, S,or O; Y is O; and R⁴ is a hydrogen atom, or a straight-chain atoms,—XC(═Y)Z—, —X—, or —XSO₂, wherein X is NR⁴; Y is O or S; X is NR⁴ or O;and R⁴ is a hydrogen atom, or a straight-chain or branched-chain alkylgroup having from 1 to 5 carbon atoms; B is a straight-chain alkylenegroup having from 1 to 3 carbon atoms, —CH═CH—, —C═C—, —CH₂O— or CH₂S—;R⁵ is the same as that in claim 4; R⁶ and R⁷ are —O— together; and R⁸ isa hydrogen atom.
 6. The method for treating cocaine dependence of claim5, wherein in the formula (I), A is —NR⁴C(═O)— or —NR⁴C(═O)O, wherein R⁴is a hydrogen atom, or a straight-chain or branched-chain alkyl grouphaving from 1 to 5 carbon atoms; B is a straight-chain alkylene grouphaving from 1 to 3 carbon atoms, —CH═CH—, or —C═C—; and R⁵ is a hydrogenatom or an organic group having a basic skeleton selected from the groupconsisting of the following formulas:

wherein the organic group optionally has at least one substituentselected from the group consisting of an alkyl group having from 1 to 5carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, ahydroxy group, a fluorine atom, a chlorine atom, a bromine atom, aniodine atom, an amino group, a nitro group, a cyano group, anisothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group,and a methylenedioxy group.
 7. A method of treating opioid μ receptoragonist dependence which comprises administering an opioid k receptoragonist or a pharmacologically acceptable acid-addition salt thereof,wherein said derivative is represented by the following formula (I):

wherein

is a double bond, or a single bond; R¹ is an alkyl group having from 1to 5 carbon atoms, a cycloalkylalkyl group having from 4 to 7 carbonatoms, a cycloalkenylalkyl group having from 5 to 7 carbon atoms, anaryl group having from 6 to 12 carbon atoms, an aralkyl group havingfrom 7 to 13 carbon atoms, an alkenyl group having from 4 to 7 carbonatoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5 carbonatoms, or a thiophen-2-ylalkyl group having from 1 to 5 carbon atoms; R²is a hydrogen atom, a hydroxy group, a nitro group, an alkanoyloxy grouphaving from 1 to 5 carbon atoms, an alkoxy group having from 1 to 5carbon atoms, an alkyl group having from 1 to 5 carbon atoms, or—NR⁹R¹⁰; R⁹ is a hydrogen atom or an alkyl group having from 1 to 5carbon atoms; R¹⁰ is a hydrogen atom, an alkyl group having from 1 to 5carbon atoms; R¹⁰ is a hydrogen atom, an alkyl group having from 1 to 5carbon atoms, or —C(═O)R¹¹ is a hydrogen atom, a hydroxy group, analkanoyloxy group having from 1 to 5 carbon atoms; A is —XC(═Y)—,—XC(═Y)Z—, —X—, or —XSO₂, wherein X, Y and Z are, independently of oneanother, NR⁴, S, or O; and R⁴ is a hydrogen atom, a straight-chain orbranched-chain alkyl group having from 1 to 5 carbon atoms, or an arylgroup having from 6 to 12 carbon atoms; and R⁴ is optionally identicalor different in the formula; B is a valence bond, a straight-chain orbranched-chain alkylene group having from 1 to 14 carbon atoms, whereinthe alkylene group is optionally substituted by one or more substituentsselected from the group consisting of an alkoxy group having from 1 to 5carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, ahydroxy group, a fluorine atom, a chlorine atom, a bromine atom, aniodine atom, an amino group, a nitro group, a cyano group, atrifluoromethyl group, a trifluoromethoxy group, and a phenoxy group,and wherein one to three methylene groups of the alkylene group isoptionally replaced with carbonyl groups, a straight-chain orbranched-chain acyclic unsaturated hydrocarbon containing from one tothree double bonds and/or triple bonds and having from 2 to 14 carbonatoms, wherein the acyclic unsaturated hydrocarbon is optionallysubstituted by one or more substituents selected from the groupconsisting of an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aminogroup, a nitro group, a cyano group, a trifluoromethyl group, atrifluoromethoxy group, and a phenoxy group and wherein one to threemethylene groups of the acyclic unsaturated hydrocarbon is optionallyreplaced with carbonyl groups, or a straight-chain or branched-chainsaturated or unsaturated hydrocarbon containing from one to fivethioether, ether, and/or amino bonds and having from 1 to 14 carbonatoms, wherein no hetero atoms are bonded directly to A, and one tothree methylene groups of the hydrocarbon is optionally replaced withcarbonyl groups; and R⁵ is a hydrogen atom or an organic group having abasic skeleton selected from the group consisting of the followingformulas:

wherein the organic group optionally has at least one substituentselected from the group consisting of an alkyl group having from 1 to 5carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, ahydroxy group, a fluorine atom, a chlorine atom, a bromine atom, aniodine atom, an amino group, a nitro group, a cyano group, anisothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group,and a methylenedioxy group; R⁶is a hydrogen atom; R⁷is a hydrogen atom,a hydroxy group, an alkoxy group having from 1 to 5 carbon atoms, or analkanoyloxy group having from 1 to 5 carbon atoms, or R⁶ and R⁷ are —O—,—CH₂—, —S— together; R⁸ is a hydrogen atom, an alkyl group having from 1to 5 carbon atoms or an alkanoyl group having from 1 to 5 carbon atoms.8. The method for treating opioid μ receptor agonist dependence of claim7, wherein in the formula (I), R¹ is a methyl group, an ethyl group, apropyl group, a butyl group, an isobutyl group, a cyclopropylmethylgroup, an allyl group, a benzyl group, or a phenethyl group; R²andR³are, independently of each other, a hydrogen atom, a hydroxy group, anacetoxy group, or a methoxy group; A is —XC(Y═)—, wherein X is NR⁴, S,or O; Y is O; and R⁴ is a hydrogen atom, or a straight-chain orbranched-chain alkyl group having from 1 to 5 carbon atoms, —XC(═Y)Z—,—X—, or —XSO₂—, wherein X is NR⁴ Y is O or S; Z is NR⁴ or O; and R⁴ is ahydrogen atom, or a straight-chain or branched-chain alkyl group havingfrom 1 to 5 carbon atoms; B is a straight-chain alkylene group havingfrom 1 to 3 carbon atoms, —CH═CH—, —C≡C—, —CH₂O— or —CH₂S—; R⁵ is thesame as that in claim 7; R⁶ and R⁷ are —O— together; and R⁸ is ahydrogen atom.
 9. The method for treating opioid μ receptor agonistdependence of claim 8, wherein in the formula (I), A is —NR⁴C(═O)— or—NR⁴C(═O)O—, wherein R⁴ is a hydrogen atom, or a straight-chain orbranched-chain alkyl group having from 1 to 5 carbon atoms; B is astraight-chain alkylene group having from 1 to 3 carbon atoms, —CH═CH—,or —C≡C—; and R⁵ is a hydrogen atom or an organic group having a basicskeleton selected from the group consisting of the following formulas:

wherein the organic group optionally has at least one substituentselected from the group consisting of an alkyl group having from 1 to 5carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aminogroup, a nitro group, a cyano group, an isothiocyanate group, atrifluoromethyl group, a trifluoromethoxy group, and a methylenedioxygroup.
 10. A method of inhibiting dopamine release which comprisesadministering an opioid K agonistic morphinan derivative or apharmacologically acceptable acid-addition salt thereof, wherein saidderivative is represented by the following formula (I):

wherein

is a double bond, or a single bond; R¹ is an alkyl group having from 1to 5 carbon atoms, a cycloalkylalkyl group having from 4 to 7 carbonatoms, a cycloalkenylalkyl group having from 5 to 7 carbon atoms, anaryl group having from 6 to 12 carbon atoms, an aralkyl group havingfrom 7 to 13 carbon atoms, an alkenyl group having from 4 to 7 carbonatoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5 carbonatoms, or a thiophen-2-ylalkyl group having from 1 to 5 carbon atoms; R²is a hydrogen atoms, a hydroxy group, a nitro group, an alkanoyloxygroup having from 1 to 5 carbon atoms, an alkoxy group having from 1 to5 carbon atoms, an alkyl group having from 1 to 5 carbon atoms, or—NR⁹R¹⁰; R⁹ is a hydrogen atom or an alkyl group having from 1 to 5carbon atoms; R¹⁰ is a hydrogen atom, an alkyl group having from 1 to 5carbon Atoms, or —C(═O)R¹¹; R¹¹ is a hydrogen atom, a phenyl group, oran alkyl group having from 1 to 5 carbon atoms; R³ is a hydrogen atom, ahydroxy group, an alkanoyloxy group having from 1 to 5 carbon atoms, oran alkoxy group having from 1 to 5 carbon atoms; A is —XC(═Y)Z—, —X—, or—XSO₂—, wherein X, Y and Z are, independently of one another, NR⁴, S, orO; and R⁴ is a hydrogen atom, a straight-chain or branched-chain alkylgroup having from 1 to 5 carbon atoms, or an aryl group having from 6 to12 carbon atoms; and R⁴ is optionally identical or different in theformula; B is a valence bond, a straight-chain or branched-chainalkylene group having from 1 to 14 carbon atoms, wherein the alkylenegroup is optionally substituted by one or more substituents selectedfrom the group consisting of an alkoxy group having from 1 to 5 carbonatoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxygroup, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom,an amino group, a nitro group, a cyano group, a trifluoromethyl group, atrifluoromethoxy group, and a phenoxy group, and wherein one to threemethylene groups of the alkylene group is optionally replaced withcarbonyl groups, a straight-chain or branched-chain acyclic unsaturatedhydrocarbon containing from one to three double bonds and/or triplebonds and having from 2 to 14 carbon atoms, wherein the acyclicunsaturated hydrocarbon is optionally substituted by one or moresubstituents selected from the group consisting of an alkoxy grouphaving from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, abromine atom, an iodine atom, an amino group, a nitro group, a cyanogroup, a trifluoromethyl group, a trifluoromethoxy group, and a phenoxygroup, and wherein one to three methylene groups of the acyclicunsaturated hydrocarbon is optionally replaced with carbonyl groups, orstraight-chain or branched-chain saturated or unsaturated hydrocarboncontaining from one to five thioether, ether, and/or amino bonds andhaving from 1 to 14 carbon atoms, wherein no hetero atoms are bondeddirectly to A, and one to three methylene groups of the hydrocarbon isoptionally replaced with carbonyl groups; and R⁵ is a hydrogen atom oran organic group having a basic skeleton selected from the groupconsisting of the following formulas:

wherein the organic group optionally has at least one substituentselected from the group consisting of an alkyl group having from 1 to 5carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aminogroup, a nitro group, a cyano group, an isothiocyanate group, atrifluoromethyl group, a trifluoromethoxy group, and a methylenedioxygroup; R⁶ is a hydrogen atom; R⁷ is a hydrogen atom, a hydroxy group, analkoxy group having from 1 to 5 carbon atoms, or an alkanoyloxy grouphaving from 1 to 5 carbon atoms, or R⁶ and R⁷ are —O—, —CH₂—, —S—together; R⁸ is a hydrogen atom, an alkyl group having from 1 to 5carbon atoms, or an alkanoyl group having from 1 to 5 carbon atoms. 11.The method of inhibiting dopamine-release of claim 10, wherein in theformula (I), R¹ is a methyl group, an ethyl group, a propyl group, abutyl group, an isobutyl group, a cyclopropylmethyl group, an allylgroup, a benzyl group, or a phenethyl group; R² and R³ are,independently of each other, a hydrogen atom, a hydroxy group, anacetoxy group, or a methoxy group; A is —XC(═Y)—, wherein X is NR⁴, S,or O; Y is O; and R⁴ is a hydrogen atom, or a straight-chain orbranched-chain alkyl group having from 1 to 5 carbon atoms, —XC(═Y)Z—,—X—, or —XSO₂—, wherein X is NR⁴; Y is O or S; Z is NR⁴ or O; and R⁴is ahydrogen atom, or a straight-chain or branched-chain alkyl group havingfrom 1 to 5 carbon atoms; B is a straight-chain alkylene group havingfrom 1 to 3 carbon atoms, —CH═CH—, CH₂O— or —CH₂S—; R⁵ is the same asthat in claim 10; R⁶ and R⁷ are —O— together; and R⁸ is a hydrogen atom.12. The method of inhibiting dopamine-release inhibitor of claim 11,wherein in the formula (I), A is —NR⁴C(═O)— or —NR⁴C(═O)O—, wherein R⁴is a hydrogen atom, or a straight-chain or branched-chain alkyl grouphaving from 1 to 5 carbon atoms; B is a straight-chain alkylene grouphaving from 1 to 3 carbon atoms, —CH═CH—, or —C═C═—; and R⁵ is ahydrogen atom or an organic group having a basic skeleton selected fromthe group consisting of the following formulas:

wherein the organic group optionally has at last one substituentselected from the group consisting of an alkyl group having from 1 to 5carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, analkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, afluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aminogroup, a nitro group, a cyano group, an isothiocyanate group, atrifluoromethyl group, a trifluoromethoxy group, and a methylenedioxygroup.
 13. The method of inhibiting dopamine-release of claim 12,wherein diseases to be treated include nicotine dependence, cocainedependence, opioid μ receptor agonist dependence, alcohol dependence,stimulant dependence, central nervous system sedative dependence, andhallucinogen dependence.